The proposed project is aimed at studying aspects of the mechanism(s) whereby certain environmental factors act as promoters of liver carcinogenesis. Low levels of dietary phenobarbital (PB), or feeding a diet devoid of a single nutritive factor, choline, both strongly promote the induction of liver tumors by chemical carcinogens in rats. Addition of low levels of PB to the choline-devoid (CD) diet results in a synergistic promoting action. Available evidence indicates that the promoters act, basically, by affecting the proliferation of liver target cells, initiated by a chemical carcinogen, and by stimulating their evolution to preneoplastic and neoplastic lesions. These effects could result from the promoters acting directly on the initiated cells, or indirectly, by creating a local micro-environment conducive to the proliferation and evolution of the initiated cells. Normal rat liver contains substances which stimulate or inhibit, respectively, hepatic cell proliferation. The balance between these substances is thought to participate in the regulation of normal liver growth. The studies proposed in this project are designed to gain a better understanding of the nature of these endogenous hepatic substances, and to explore whether and to what extent the liver carcinogenesis promoting action of PB and of a CD diet, either alone or in combination, is mediated by an alteration of the balance of these substances.